title: Novel complex re-arrangement of ARG1 commonly shared by unrelated patients with hyperargininemia.
abstract: BACKGROUND
  Hyperargininemia is a very rare progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. Until now, some mutations were reported worldwide and none of them were of Southeast Asian origins. Furthermore, most reported mutations were point mutations and a few others deletions or insertions.
  
  
  OBJECTIVE
  This study aims at identifying the disease-causing mutation in the ARG1 gene of Malaysian patients with hyperargininemia.
  
  
  METHODS
  We employed a series of PCR amplifications and direct sequencing in order to identify the mutation. We subsequently used quantitative real-time PCR to determine the copy number of the exons flanking the mutation. We blasted our sequencing data with that of the reference sequence in the NCBI in order to obtain positional insights of the mutation.
  
  
  RESULTS
  We found a novel complex re-arrangement involving insertion, inversion and gross deletion of ARG1 (designated g.insIVS1+1899GTTTTATCAT;g.invIVS1+1933_+1953;g.delIVS1+1954_IVS2+914;c.del116_188;p.Pro20SerfsX4) commonly shared by 5 patients with hyperargininemia, each originating from different family. None of the affected families share known relationship with each other, although four of the five patients were known to have first-cousin consanguineous parents.
  
  
  CONCLUSIONS
  This is the first report of complex re-arrangement in the ARG1. Further analyses showing that the patients have shared the same geographic origin within the northeastern part of Malaysia prompted us to suggest a simple molecular screening of hyperargininemia within related ethnicities using a long-range PCR.
authors.affiliation: Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.
authors.forename: Jafar
authors.initials: J
authors.lastname: Mohseni
authors.forename: Chia
authors.initials: C
authors.lastname: Boon Hock
authors.forename: Che
authors.initials: C
authors.lastname: Abdul Razak
authors.forename: Syah Nor Iman
authors.initials: SN
authors.lastname: Othman
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Hayati
authors.forename: Winnie Ong
authors.initials: WO
authors.lastname: Peitee
authors.forename: Muzhirah
authors.initials: M
authors.lastname: Haniffa
authors.forename: Bin Alwi
authors.initials: BA
authors.lastname: Zilfalil
authors.forename: Rowani
authors.initials: R
authors.lastname: Mohd Rawi
authors.forename: Lock-Hock
authors.initials: LH
authors.lastname: Ngu
authors.forename: Teguh Haryo
authors.initials: TH
authors.lastname: Sasongko
mesh_terms: D001119:Arginase / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004247:DNA; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D020162:Hyperargininemia / Q000235:genetics*; D007223:Infant; D008296:Malaysia; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004247:DNA; D001119:Arginase
keywords: ARG1; ATPase; Adenosine Triphosphatase; Arginase 1 Gene; Arginase deficiency; Complex re-arrangement; DNA; DeoxyriboNucleic Acid; GABA; Gamma-AminoButyric Acid; Hyperargininemia; NCBI; NHLBI; National Center for Biotechnology Information; National Heart, Lung and Blood Institute; OMIM; Online Mendelian Inheritance in Man; PCR; Polymerase Chain Reaction; RefSeq; Reference Sequence; Sdn. Bhd; Sendirian Berhad (Co. Ltd. in Malaysian); dNTP; deoxyribuNucleotide TriPhosphate; qPCR; quantitative real-time PCR